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(Circulation. 1999;99:224-229.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
In Vivo Formation of 8-Iso-Prostaglandin F2
and Platelet Activation in Diabetes Mellitus
Effects of Improved Metabolic Control and Vitamin E Supplementation
From the Departments of Medicine and Aging (G.D., A.C., A.M., S.S., E.P., E.V., F. Costantini, F. Capani, C.P.) and Biomedical Sciences (T.B.), University of Chieti "G. D'Annunzio" School of Medicine; the Division of Internal Medicine, Civil Hospital of Popoli (A.F.); and the Department of Pharmacology (G.C.), Catholic University School of Medicine; Rome, Italy.
Correspondence to Dr Patrono, Department of Medicine and Aging, University of Chieti "G. D'Annunzio," via dei Vestini 31, 66013 Chieti, Italy. E-mail cpatrono{at}unich.it
Background—Diabetes mellitus
(DM) is associated with enhanced lipid peroxidation and persistent
platelet activation. We tested the hypothesis that the in vivo
formation of the F2-isoprostane
8-iso-prostaglandin (PG)F2
, a bioactive
product of arachidonic acid peroxidation, is
enhanced in DM and contributes to platelet activation.
Methods and Results—Urine samples were obtained from 85 diabetic
patients and 85 age- and sex-matched healthy subjects for measurement
of immunoreactive 8-iso-PGF2 and
11-dehydro-thromboxane B2 (TXM), an in vivo
index of platelet activation. Sixty-two had non–insulin-dependent
(NID)DM, and 23 had insulin-dependent (ID) DM. Vitamin E
supplementation, metabolic control, and
cyclooxygenase inhibitors were used to
investigate the mechanisms of formation of 8-iso-PGF2 in
this setting. Urinary 8-iso-PGF2 excretion was
significantly higher (P=0.0001) in NIDDM patients
(419±208 pg/mg creatinine; range 160 to 1014) than in
age-matched control subjects (208±92; 41 to 433). Urinary
8-iso-PGF2 was linearly correlated with blood glucose
and urinary TXM. 8-iso-PGF2 excretion was also
significantly (P=0.0001) higher in IDDM patients
(400±146; 183 to 702) than in control subjects (197±69; 95 to 353).
Vitamin E supplementation (600 mg/d for 14 days) was associated with a
statistically significant reduction in both urinary
8-iso-PGF2 (by 37%) and TXM (by 43%) in 10 NIDDM
patients. Improved metabolic control was associated with a
significant (P=0.0001) reduction in
8-iso-PGF2 and TXM excretion by 32% and 41%,
respectively, in 21 NIDDM patients. 8-iso-PGF2 was
unchanged after 2-week dosing with aspirin and indobufen despite
profound suppression of TXM excretion.
Conclusions—We conclude that DM is associated with increased formation of F2-isoprostanes, as a correlate of impaired glycemic control and enhanced lipid peroxidation. This may provide an important biochemical link between impaired glycemic control and persistent platelet activation. These results provide a rationale for dose-finding studies of antioxidant treatment in diabetes.
Key Words: diabetes mellitus • platelets • lipids • thromboxane • antioxidants
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R. De Caterina, F. Cipollone, F. P. Filardo, M. Zimarino, W. Bernini, G. Lazzerini, T. Bucciarelli, A. Falco, P. Marchesani, R. Muraro, et al. Low-Density Lipoprotein Level Reduction by the 3-Hydroxy-3-Methylglutaryl Coenzyme-A Inhibitor Simvastatin Is Accompanied by a Related Reduction of F2-Isoprostane Formation in Hypercholesterolemic Subjects: No Further Effect of Vitamin E Circulation, November 12, 2002; 106(20): 2543 - 2549. [Abstract] [Full Text] [PDF]
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L. Fontana, C. Giagulli, L. Cominacini, A. F. Pasini, P. Minuz, A. Lechi, A. Sala, and C. Laudanna {beta}2 Integrin-Dependent Neutrophil Adhesion Induced by Minimally Modified Low-Density Lipoproteins Is Mainly Mediated by F2-Isoprostanes Circulation, November 5, 2002; 106(19): 2434 - 2441. [Abstract] [Full Text] [PDF]
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R. J Woodman, T. A Mori, V. Burke, I. B Puddey, G. F Watts, and L. J Beilin Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension Am. J. Clinical Nutrition, November 1, 2002; 76(5): 1007 - 1015. [Abstract] [Full Text] [PDF]
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G. Davi, M. T. Guagnano, G. Ciabattoni, S. Basili, A. Falco, M. Marinopiccoli, M. Nutini, S. Sensi, and C. Patrono Platelet Activation in Obese Women: Role of Inflammation and Oxidant Stress JAMA, October 23, 2002; 288(16): 2008 - 2014. [Abstract] [Full Text] [PDF]
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U. Riserus, S. Basu, S. Jovinge, G. N. Fredrikson, J. Arnlov, and B. Vessby Supplementation With Conjugated Linoleic Acid Causes Isomer-Dependent Oxidative Stress and Elevated C-Reactive Protein: A Potential Link to Fatty Acid-Induced Insulin Resistance Circulation, October 8, 2002; 106(15): 1925 - 1929. [Abstract] [Full Text] [PDF]
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H.-Y. Huang, L. J Appel, K. D Croft, E. R Miller III, T. A Mori, and I. B Puddey Effects of vitamin C and vitamin E on in vivo lipid peroxidation: results of a randomized controlled trial Am. J. Clinical Nutrition, September 1, 2002; 76(3): 549 - 555. [Abstract] [Full Text] [PDF]
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R. D. Hoeldtke, K. D. Bryner, D. R. McNeill, G. R. Hobbs, J. E. Riggs, S. S. Warehime, I. Christie, G. Ganser, and K. Van Dyke Nitrosative Stress, Uric Acid, and Peripheral Nerve Function in Early Type 1 Diabetes Diabetes, September 1, 2002; 51(9): 2817 - 2825. [Abstract] [Full Text] [PDF]
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M. A. Forgione, A. Cap, R. Liao, N. I. Moldovan, R. T. Eberhardt, C. C. Lim, J. Jones, P. J. Goldschmidt-Clermont, and J. Loscalzo Heterozygous Cellular Glutathione Peroxidase Deficiency in the Mouse: Abnormalities in Vascular and Cardiac Function and Structure Circulation, August 27, 2002; 106(9): 1154 - 1158. [Abstract] [Full Text] [PDF]
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 J. D. Krier, M. Rodriguez-Porcel, P. J. M. Best, J. C. Romero, A. Lerman, and L. O. Lerman Vascular responses in vivo to 8-epi PGF2alpha in normal and hypercholesterolemic pigs Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R303 - R308. [Abstract] [Full Text] [PDF]
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E. D. Aymong, M. J. Curtis, M. Youssef, M. M. Graham, L. Shewchuk, W. Leschuk, and T. J. Anderson Abciximab Attenuates Coronary Microvascular Endothelial Dysfunction After Coronary Stenting Circulation, June 25, 2002; 105(25): 2981 - 2985. [Abstract] [Full Text] [PDF]
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K. Foo and A. D Timmis Review: Managing the diabetic patient with angina The British Journal of Diabetes & Vascular Disease, May 1, 2002; 2(3): 169 - 175. [Abstract] [PDF]
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T. Ide, H. Tsutsui, N. Ohashi, S. Hayashidani, N. Suematsu, M. Tsuchihashi, H. Tamai, and A. Takeshita Greater Oxidative Stress in Healthy Young Men Compared With Premenopausal Women Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 438 - 442. [Abstract] [Full Text] [PDF]
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S. Devaraj, A. V. C. Chan Jr., and I. Jialal {alpha}-Tocopherol Supplementation Decreases Plasminogen Activator Inhibitor-1 and P-Selectin Levels in Type 2 Diabetic Patients Diabetes Care, March 1, 2002; 25(3): 524 - 529. [Abstract] [Full Text] [PDF]
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M. J. Sampson, N. Gopaul, I. R. Davies, D. A. Hughes, and M. J. Carrier Plasma F2 Isoprostanes: Direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes Diabetes Care, March 1, 2002; 25(3): 537 - 541. [Abstract] [Full Text] [PDF]
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A. Nitenberg, S. Ledoux, P. Valensi, R. Sachs, and I. Antony Coronary Microvascular Adaptation to Myocardial Metabolic Demand Can Be Restored by Inhibition of Iron-Catalyzed Formation of Oxygen Free Radicals in Type 2 Diabetic Patients Diabetes, March 1, 2002; 51(3): 813 - 818. [Abstract] [Full Text] [PDF]
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F. Violi, L. Iuliano, and G. A. FitzGerald Reply J. Am. Coll. Cardiol., February 6, 2002; 39(3): 554 - 555. [Full Text] [PDF]
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M. S. Sabatine and E. Braunwald Will Diabetes Save the Platelet Blockers? Circulation, December 4, 2001; 104(23): 2759 - 2761. [Full Text] [PDF]
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A Liguori, P Abete, J.M Hayden, F Cacciatore, F Rengo, G Ambrosio, D Bonaduce, M Condorelli, P.D Reaven, and C Napoli Effect of glycaemic control and age on low-density lipoprotein susceptibility to oxidation in diabetes mellitus type 1 Eur. Heart J., November 2, 2001; 22(22): 2075 - 2084. [Abstract] [PDF]
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J. I. Osende, J. J. Badimon, V. Fuster, P. Herson, P. Rabito, R. Vidhun, A. Zaman, O. J. Rodriguez, E. I. Lev, U. Rauch, et al. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1307 - 1312. [Abstract] [Full Text] [PDF]
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S. Devaraj, S. V. Hirany, R. F. Burk, and I. Jialal Divergence between LDL Oxidative Susceptibility and Urinary F2-Isoprostanes as Measures of Oxidative Stress in Type 2 Diabetes Clin. Chem., November 1, 2001; 47(11): 1974 - 1979. [Abstract] [Full Text] [PDF]
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S. T. Davidge Prostaglandin H Synthase and Vascular Function Circ. Res., October 12, 2001; 89(8): 650 - 660. [Abstract] [Full Text] [PDF]
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J.-L. CRACOWSKI, C. CRACOWSKI, G. BESSARD, J.-L. PEPIN, J. BESSARD, C. SCHWEBEL, F. STANKE-LABESQUE, and C. PISON Increased Lipid Peroxidation in Patients with Pulmonary Hypertension Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 1038 - 1042. [Abstract] [Full Text] [PDF]
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G. Davi, G. Di Minno, A. Coppola, G. Andria, A. M. Cerbone, P. Madonna, A. Tufano, A. Falco, P. Marchesani, G. Ciabattoni, et al. Oxidative Stress and Platelet Activation in Homozygous Homocystinuria Circulation, September 4, 2001; 104(10): 1124 - 1128. [Abstract] [Full Text] [PDF]
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